Is CES3 p.Pro142Leu (c.425C>T) pathogenic?

CES3 p.Pro142Leu (c.425C>T) is classified Uncertain significance in CES3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.4455); Ultra-rare (popmax 0.0187%, afr).

How common is CES3 p.Pro142Leu (c.425C>T) in the general population?

CES3 p.Pro142Leu (c.425C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

What do computational predictors say about CES3 p.Pro142Leu (c.425C>T)?

AlphaMissense predicts ambiguous (score 0.4455) — an in-silico prediction, not a clinical call.

CES3 p.Pro142Leu

c.425C>T · VCV4226749

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4455 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4455	ambiguous
REVEL	0.191	benign-leaning
SaProt	LLR -8.73	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.30 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.2	GERP 0.38, phastCons 0.84
Regional constraint	o/e 0.87	unconstrained · MANE · 12 kb · p 0.00037 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/75,042 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00903%

Overall 0.00496% 80/1,614,064 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,360
Admixed American	0.00666%	15,004
European (non-Finnish)	0.00483%	20,702
Remaining individualsnot grpmax-eligible	0.0032%	31,254
East Asian	0.00223%	44,886
South Asian	0.0022%	45,538

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CES3
Protein: p.Pro142Leu
Coding: c.425C>T
MANE Select: NM_024922
Type: single nucleotide variant
Location: chr16:66963628 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.89

Full CES3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CES3 p.Ala133Pro Uncertain significance ★ ⚠ same type
CES3 p.Ala137Thr Uncertain significance ★ ⚠ same type
CES3 p.Ala214Val Uncertain significance ★ ⚠ same type
CES3 p.Ala230Gly Uncertain significance ★ ⚠ same type
CES3 p.Ala244Thr Uncertain significance ★ ⚠ same type
CES3 p.Ala408Glu Uncertain significance ★ ⚠ same type
CES3 p.Ala449Glu Uncertain significance ★ ⚠ same type
CES3 p.Ala449Val Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ces3-p-pro142leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown